5beta-pregn-1-ene-3, 20-dione and 20-ketals thereof



United States Patent 2,913,457 /8-PREGN-1-ENE-3,20-DIONE AND ZO-KETALSTHEREOF Gunther S. Fonken, Kalamazoo, and Herbert C. Murray,

Barry Township, Barry County, Mich., assignors to The Upjohn Company,Kalamazoo, Mich., a corporation of Delaware No Drawing. Originalapplication May 1, 1959, Serial No. 810,233. Divided and thisapplication July 9, 1959, Serial No. 825,883

3 Claims. (Cl. 260-23955) This invention relates to certain novelsteroids, more particularly 5p-pregn-l-ene-3,11,20-trione and the 20-ketals thereof represented by the formula:

wherein R is lower-alkylene containing from 2 to 8 carbon atoms and from2 to 3 carbon atoms in the chain, e.g., ethylene, l-methylethylene,propylene, l-methylpropylene, 2,2-dimethylpropylene, l-ethylethylene,l-propylethylene, l-butylethylene, l-amylethylene. Especially preferredare the 20-ethylene ketals.

513-pregn-l-ene-3,l1,20-trione possesses useful pharmacologicalproperties, including central nervous system depressant activity,rendering the compound useful as an anesthetic, e.g., during themanipulation of and experimentation with laboratory animals includingrabbits, mice and rats. Administration can be by the usual dosage forms,including pills, tablets, capsules, syrups or elixirs for oral use, orin the known liquid forms which are adaptable for injection.

The following preparations and example are illustrative of the productsof the present invention, but are not to be construed as limiting.

PREPARATION 1 Pregnenolone ZO-ethylene ketal A mixture of 10 g. ofpregnenolone, 20 ml. of ethylene glycol, 0.5 g. of p-toluenesulfonicacid monohydrate and 250 ml. of benzene was refluxed with stirring forabout 7 hours, using a Dean-Stark water trap. The cooled mixture waswashed with aqueous sodium bicarbonate after dissolving precipitatedsteroid with methanol. The separated benzene layer was evaporated untilonly methanol remained and the resulting slurry was filtered to give12.3 g of pregnenolone 20-ethylene ketal which was re crystallized fromacetone containing a trace of pyridine to give crystals melting at167-170 C.

PREPARATION 2 513-pregnane-3J1 ,20-trione 20-ethylene ketal 100 g. of3a-hydroxy-5B-pregnane-l1,20-di0ne was converted to the corresponding20-ethylene ketal in the manner described in Preparation 1.

75.5 g. of the thus-produced 3a-hydroxy-5fi-pregnane- 11,20-dioneZO-ethylene ketal was dissolved in 100 ml. of pyridine, diluted with2,000 ml. of tertiary butyl alcohol, and stirred overnight at roomtemperature with 41.3 g. of N-bromoacctamide. A solution of 25 g. of

Patented Nov. 17, 1959 sodium sulfite in 350 ml. of water was added andthe solution evaporated at reduced pressure until most of the tertiarybutyl alcohol was removed. The resulting precipitate was filtered andthe cake washed with aqueous sodium bicarbonate, with water and thendried. The thusobtained 5B-pregnane-3,11,20-trione ZO-ethylene ketal wasrecrystallized from a mixture of acetone and hexanes (Skellysolve B) togive crystals melting at ISO-153 C.

EXAMPLE 1 Sfl-pregn-I-ene-i]1,20-trione and ZO-ethylene ketal 10 l. ofmedium consisting of 1% dextrose (Cerelose) and 2% corn steep liquor of60% solids, was adjusted to pH 4.9 with sodium hydroxide. 1 ml. ofsilicon oil anti-foaming agent (Dow-Corning XC-l20) was added. Themedium was steam sterilized at 20 lbs. pressure for minutes at C. Uponcooling, the sterile medium was inoculated with a 72-hour growth, fromspores, of Septomyxa afiim's (ATCC 6737). The medium was agitated, andsparged with sterile air at the rate of 0.5 l. of air per minute. Afterculturing at room temperature for 48 hours at 28 C., the pH was 7.5. Tothis 48- hour culture there was added 2.0 g. of pregnane-3,l1,20- trione20-ethylene ketal plus 50 mg. of 3-ketobisnor-4- cholen-22-aldehyde as aconversion assistant in 30 ml. of N,N-dimethylformamide. The flask wasrinsed with '10 m. of acetone which was also added to the medium.Fermentation of the steroid was maintained for 48 hours, at the end ofwhich time the pH was 8.15. The fermentation broth was strained throughgauze to separate the mycelium. The filtrate was extracted withmethylene chloride. The methylene chloride extracts were distilled underreduced pressure to a volume of about 1 l. and evaporated in air. Theresidual solids were chromatographed through a 2.8 x 36 cm. column ofmagnesium silicate (Florisil). Hexanes (Skellysolve B) plus 5% acetoneeluted 5B-pregn-l-ene-3,1l,20- trione 20-ethylene ketal which wasrecrystallized from a mixture of hexanes and acetone to give 0.87 g. ofcrystals melting at 204-206 C., having a A 225 In a 8800 A solution of0.50 g. of 5fl-pregn-l-ene-3,l1,20-trione 20-ethylene ketal in 25 ml. ofmethanol was hydrolyzed by the addition of 5 ml. of N-hydrochloric acidand permitting the reaction mixture to stand at room temperature forseveral hours. The hydrolyzed solution Was concentrated to a smallvolume and cooled, whereupon crystals of 5,3-pregn-1-ene-3,11,20-trioneformed and were separated by filtration. The compound has amelting pointof 152-162 C.

This application is a division of our application 810,233, filed May 1,1959.

wherein R is lower-alkylene containing from 2 to 8 carbon atoms and from2 to 3 carbon atoms in the chain.

2. 5B-pregn-l-ene-3,l1,20-trione 20-ethylene ketal.

3, 5,B-pregn-1-ene-3,11,20-trione.

No references cited.

1. A COMPOUND REPRESENTED BY THE FORMULA: